OBJECTIVE:
To compare the neurobehavior of small (SGA) and adequate (AGA) for gestational
age full-term neonates born to adolescent mothers.METHODS:This prospective cross-sectional study included full-term newborn
infants aged 24-72 hours, free from central nervous system malformations and
born to adolescent mothers at a single center in Brazil. Infants were assessed
with the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) for:
habituation, attention, arousal, regulation, handling, quality of movement,
excitability, lethargy, nonoptimal reflexes, asymmetry, hypertonia, hypotonia,
and stress/abstinence signals. The chi-square test and analysis of variance
were used to compare SGA and AGA infants. Multivariate regression was used to
analyze factors associated with the score of each NNNS variable.RESULTS: Of 3,685 infants born in the study hospital, 928 (25%) had adolescent
mothers. Of these, 477 infants met the inclusion criteria: 419 (88%) were AGA
and 58 (12%) were SGA. Univariate analysis did not show any differences between
AGA and SGA neonates in terms of NNNS variables. Multivariate analysis showed
that SGA neonates born by vaginal delivery had lower scores for quality of movements
than those born by caesarean section. The SGA neonates born with local or without
anesthesia had higher scores for excitability than those born with spinal anesthesia.
Additionally, female SGA neonates had lower scores for stress/abstinence signals
than males.CONCLUSION: SGA neonates born to adolescent mothers showed poorer quality
of movements, more excitability and more signals of stress in association with
sex of infant and variables related to delivery.

Keywords:
Behavior, pregnancy in adolescence, infant, newborn.

Introduction

Small for gestational
age (SGA) newborns are the result of intrauterine growth restriction, which
can be triggered by a series of factors inherent to the health of the mother
and fetus, in addition to those related to the family's socioeconomic
conditions. Pregnancy during adolescence, the absence of a fixed partner, low
educational level, insufficient prenatal care, the use of both legal and illegal
drugs, exposure to sexually transmitted diseases, violence and psychological
disorders can, in combination or in isolation, lead to inadequate fetal growth.1,2
Regarding teenager pregnancies, they are associated to violence exposure and
to mental disorders. Violence during pregnancy is reported to be associated
with the birth of SGA infants, while mental diseases are associated with prematurity.3
On the other hand, pregnancy during adolescence is not alone a risk factor for
low birth weight when the influence of unfavorable clinical, gestational and
psychosocial factors is subtracted.4

It is known that
intrauterine malnutrition may alter the anatomic and functional maturation of
the central nervous system. Chronic placental insufficiency, which results in
fetal growth restriction, leads to deficits in neural connections and myelination
and alters the function of auditory and visual systems during the postnatal
period.5 Volumetric studies using magnetic resonance have indicated
reduced grey matter in full-term SGA neonates, with the hippocampus being especially
vulnerable to the effects of placental insufficiency.6 Furthermore,
cortical growth is compromised in fetuses with severely restricted intrauterine
growth, with reduced numbers of cells in the cerebral cortex.7 These
changes in the growth and development of the central nervous system can trigger
neurobehavioral alterations that are already detectable in the first days of
life.8

The classic description
of the SGA newborn includes increased motor ability, exaggerated responses to
reflex tests, prolonged periods in a state of arousal and more appetite than
newborns of the same weight but younger gestational ages.9 However,
studies of specific aspects of the neurological performance of SGA infants,
such as muscle tone assessment by objective methods, indicate the presence of
reduced muscle tone.10 Assessment of the global neurobehavioral performance
of infants born at full term with intrauterine growth restriction, compared
with appropriate for gestational age (AGA) neonates, demonstrates worse performance
in items related to orientation to stimuli, motor responses and reflexes, in
addition to reduced muscle tone, during the first days of life. SGA infants
spend less time awake and need more comforting maneuvers, and they have problems
with self-quieting.11-14Nevertheless, these alterations are not observed
in a uniform manner and some authors have observed better orientation in response
to external stimuli among SGA newborn infants.15-16

The neurobehavior
of SGA newborn infants, in addition to having been little studied, is also complicated
by a lack of homogeneity in terms of the definition of "small for gestational
age” and of neurobehavioral assessment methods. In this context, this
study goal was to compare the neurobehavioral of SGA and AGA full-term infants
born to adolescent mothers with the Neonatal Intensive Care Unit Neurobehavioral
Network Scale (NNNS).

Methods

This was a single-center
cross-sectional study, with prospective data collection, carried out at a tertiary
hospital in the city of São Paulo, Brazil, during the period between
July 2001 and November 2002. The study was approved by the Research Ethics Committees
at the hospital where data collection was carried out and at the educational
institution to which the researchers are affiliated and was financed by the
Fundação de Apoio à Pesquisa do Estado de São Paulo.

The patient sample
was selected based on the following inclusion criteria: signature of a free
and informed consent form by the mother, newborn infant with adolescent mother
(age 10-19 years), born full term (gestational age 37-416,7 weeks), based on
gestational age calculated from the last menstrual date or, when this information
was not available, by the New Ballard method.17

Neonates were
excluded if they exhibited one or more of the following conditions that could
interfere with neurobehavioral responses: mothers with positive serology for
congenital infections either during pregnancy or at delivery; mothers who were
given opiates, sedatives and/or anticonvulsants during the 24 hours before delivery
or general anesthetic during delivery; newborn infants who had been exposed
to tobacco, alcohol, marijuana, cocaine or other drugs during gestation; products
of multiple gestations; 1 minute Apgar score < 3 or 5 minute Apgar < 7;
newborn infants with major congenital malformations; and presence of clinical
problems on the day of data collection. Jaundiced neonates were included if
not in phototherapy at the time of the test, as were infants who had exhibited
adaptive respiratory distress, but did not need oxygen therapy and were in normal
nursery at time of the test.

The study included
interviews with the mothers and physical examination and neurobehavioral assessment
of the newborn infants. The adolescents were interviewed soon after delivery
regarding demographic, clinical, antenatal, labor and delivery data data.

The neurobehavioral
assessments of the neonates were carried out by neonatologists using the NNNS.18
The NNNS is a scale that assesses neurological integrity, behavioral function
and the presence of signals of stress and abstinence in newborns.19
The test was applied after 24 hours of life, when the stress response to delivery
has subsided, and before 72 hours of life, in a calm, dimly lit, heated room
by one of four neonatologists. One of the investigators (MMCB) was certified
to apply the NNNS at the Women and Infants Hospital, Brown University (Rhode
Island, USA) and trained the other three neonatologists. Reliability of the
NNNS was verified by simultaneous weekly applications by the lead researcher
and each of the three neonatologists, throughout the study, in order to detect
and correct possible discrepancies. After the assessment, the items analyzed
were grouped into the 13 variable categories described by Boukydis et al.19
as follows: habituation, attention, arousal, control, handling, quality of movement,
excitability, lethargy, nonoptimal reflexes, asymmetry, hypertonia, hypotonia,
and stress/abstinence signals.

The information
on the adolescent mothers' consumption of legal and illegal drugs during
pregnancy was obtained by interview and by toxicological analysis of samples
of the mothers' hair and newborns' meconium. The mothers were interviewed
by psychologists soon after delivery. Three centimeter samples of the mothers'
hair were taken from close to the scalp to be assayed for marijuana and cocaine
metabolites by semi-quantitative enzymatic immunoassay, with confirmation by
gas chromatography and/or mass spectrometry. The sample was considered positive
when both results, screening and confirmation, were positive. Intrauterine marijuana
and/or cocaine exposure was detected by toxicological analysis of a meconium
sample collected during the first 2 days of life and processed by semi-quantitative
homogenous enzymatic immunoassay. With relation to tobacco, newborn infants
were excluded if their mothers had smoked any number of cigarettes during pregnancy.
With relation to alcohol, neonates were only included in the sample if their
mothers stated that they had not drunk during pregnancy or just once, on a special
occasion. All newborn infants exposed to illegal drugs were excluded, irrespective
of the frequency or quantity of maternal consumption.

The newborn infants
were divided into two groups depending on the appropriateness of their birth
weight to their gestational age, according to the curve described by Alexander
et al.20 Birth weights between percentiles 10 and 90 for gestational
age where defined as AGA and weights below the 5th percentile as SGA. Newborn
infants with birth weights between the 5th and 10th percentiles were excluded
from the study. AGA and SGA neonates were compared using the chi-square test
for categorical variables and Student's t test for numerical variables.

Analysis of variance
(ANOVA) and multivariate linear regression were applied to identify whether
intrauterine growth restriction influenced the scores for NNNS variables, controlling
for other factors that could affect the newborns' behavior. Each of the 11 numerical
variables from the NNNS (habituation, attention, arousal, control, handling,
quality of movement, excitability, lethargy, nonoptimal reflexes, asymmetry
and signals of stress and abstinence) were taken as dependent variables and
the following as independent variables: appropriateness of weight to gestational
age (AGA vs. SGA), anesthesia during delivery (none/local vs. regional block),
type of delivery (vaginal vs. caesarean), sex, gestational age, birth weight,
1st and 5th minute Apgar scores and age of the newborn at neurobehavioral assessment.
Two of the 13 NNNS variables were analyzed as qualitative categories: hypertonia
and hypotonia. For both, the effect of intrauterine growth restriction was determined
by logistic regression, with the independent variables being the same used for
the multivariate linear regression and ANOVA.

The sample size
was determined based on the need to study 15 to 20 newborn infants per independent
variable to be assessed in the multivariate linear regression or logistic regression.
Since all of the 13 variables on the NNNS were considered dependent variables
and each of them was tested for associations with nine independent variables,
the minimum sample size was 135 to 180 newborn infants. Statistical procedures
were carried out using SPSS 10.0 and significance was set at p < 0.05 for
all tests.

Results

A total of 792
infants were born at full term during the study period and 264 of these were
excluded due to one or more of the conditions defined in the exclusion criteria.
Intrauterine growth restriction was detected in 109 of the remaining 528 neonates,
51 of whom had weights between the fifth and 10th percentiles for gestational
age. Therefore, the final study sample comprised 477 patients: 419 AGA and 58
SGA infants.

Both groups were
similar in terms of maternal characteristics, with the exception of prenatal
care and anesthesia for delivery. The mothers of the SGA infants attended fewer
prenatal care visits and more frequently received regional anesthesia (Table
1).

In relation to
neonatal characteristics, there were fewer males and mean gestational age, birth
weight and head circumference were lower in the SGA group (Table
2).

The neurobehavioral
assessment was applied by four previously trained neonatologist, with the number
of assessments carried out by each being 106 (22.2%), 114 (23.9%), 123 (25.8%)
and 134 (28.1%). There were no differences between the AGA and SGA groups regarding
the age at which the newborn infants were examined, duration of assessment or
time elapsed between the last feed and starting the assessment (Table
2).

In the multivariate
analysis there was no effect from being born SGA on the following items of the
neurobehavioral assessment: habituation, attention, arousal, control, handling,
lethargy, nonoptimal reflexes, asymmetry, hypertonia or hypotonia. However,
being SGA did have an impact on the following variables: quality of movement,
excitability and signals of stress and abstinence.

For "quality
of movement”, there was an interaction between type of delivery and appropriateness
of weight to gestational age (p = 0.057). Those SGA neonates who were delivered
vaginally had lower scores than the caesarean-born infants (5.01±0.74
vs. 5.34±0.13), controlling for type of anesthesia and sex. This difference
was not observed among the AGA.

With relation
to "excitability”, there was an interaction between type of anesthesia
and appropriateness of weight to gestational age (p = 0.038). SGA neonates born
with local anesthesia or without anesthesia scored higher on this variable than
SGA born under regional anesthesia (3.18±0.35 vs. 2.09±0.29),
controlling for type of delivery and sex. This difference was not observed among
the AGA.

Finally, with
relation to "signs of stress/abstinence”, an interaction was detected
between sex of infant and appropriateness of weight to gestational age (p =
0.039). Female SGA patients exhibited less signals of stress and/or abstinence
than their male counterparts (0.059±0.008 vs. 0.093±0.012), controlling
for type of anesthesia and delivery. This difference was not observed among
the AGA.

Discussion

Approximately
900,000 adolescents get pregnant every year in United States21 and,
in 2004, 22% of the 3,026,548 live births in Brazil ocurred among adolescent
mothers.22 Adolescent pregnancy is associated with low socioeconomic
status, absence of a fixed partner, a lack of access to education in general
and health education in particular and risk behaviors such as the use of tobacco,
alcohol and drugs, among others. Many of these factors, in isolation or together,
can lead to intrauterine growth restriction.1,2

The 14% (109/792)
frequency of SGA newborn infants observed in this sample of full-term newborn
infants, although elevated, has also been observed in other Brazilian studies.23,24
This high proportion of SGA is observed in our country when North-American intrauterine
growth curves are used. It is controversial whether it reflects an elevated
prevalence of intrauterine malnutrition or simply a different constitutional
pattern among the Brazilian population.20 In order to avoid including
in the sample newborn infants with weights below the North American standard
for gestational age who did not suffer intrauterine growth restriction, it was
decided to study just those SGA infants below the fifth percentile of the reference
scale, excluding those whose birth weights were between the 5th and the 10th
percentiles.

With relation
to the neurobehavior of SGA neonates, Als et al. assessed 10 vaginally-delivered
full-term neonates with low weights on their first, third, fifth and 10th days
of life. Compared with heavier babies, patients exhibited worse performance
in interactive behavior, with less capacity to respond to stimuli.11
Lester et al. studied 37 healthy full-term neonates on their 2nd-3rd day of
life. Those with weight, length or weight below the 10th percentile performed
worse on items related to orientation to stimuli, motor responses and reflexes,
in addition to being less alert.25 Costas i Moragas et al. assessed
41 SGA infants born at full term at 3 days of life, comparing them with full-term
babies with birth weights between the 25th and 75th percentiles for gestational
age. The SGA infants exhibited lower capacity to respond to external stimuli,
less motor activity and muscle tone and they needed greater number of quieting
maneuvers, presenting difficulties self-quieting.13 Abrol et al.
also analyzed the behavior of 25 SGA babies born by vaginal delivery at 1, 5,
10 and 30 days of life. Compared with AGA infants, the SGA exhibited poorer
performance in all items that assessed their interaction with the environment
and in their motor performance.14 The authors attributed these findings
to changes to nervous system development and cerebral organization in newborn
infants subjected to nutritional restriction during gestation.14,25
In this study, using a scale validated for neurobehavioral assessment during
the first days of life and with established reference values,26,27
the findings differed from those described above, since, in the univariate comparisons
similar performance was observed in the 13 neurobehavioral variables examined
for both SGA and AGA infants. However, being born SGA influenced the neonatal
neurobehavioral performance in association with other factors that stress the
mother-baby pair (anesthesia and type of delivery) or with characteristics of
the infants themselves (sex).

Those SGA newborn
infants who were delivered under local anesthesia or without anesthesia were
more excitable, with greater irritability, lability of skin color and state
of arousal, tremors and startles than those delivered with regional anesthesia.
In the same way, babies with birth weights below the 5th percentile
for gestational age who were delivered vaginally exhibited poorer quality of
movements compared with those delivered by C-section. Studies with animal models
have demonstrated that the concentrations of growth factors, particularly brain-derived
neurotrophic factor, and cytokines are significantly altered in the hippocampus
of fetuses with intrauterine growth restriction and that these changes to the
mediators are amplified by acute events and may mediate neuronal and white matter
lesions.5,28 Therefore, it is possible that modifications to the
organization of the nervous system associated with intrauterine growth restriction
may be enhanced by the release of stress hormones during labor and delivery,
interfering with the neurobehavior of SGA newborn infants.

It is intriguing
that male SGA newborn infants exhibited a greater number of stress/abstinence
signals compared to females. The influence of sex on the neurobehavior of newborn
infants during the first week of life has not been systematically assessed.
However, Brown et al. analyzed neurobehavioral changes in extreme preterm infants
using the NNNS and reported that female babies exhibited better performance
than males for "quality of movement”.29 It is known that
higher levels of stress hormones are found in male newborn infants when they
are subjected to stressful procedures.30 It is possible that intrauterine
growth restriction causes different cortical growth and organization changes
during intrauterine life for male and female fetuses, depending on the predominant
hormonal influence, which would explain the neurobehavioral differences observed
in male and female SGA newborn infants during their first days of life.

This study is
subject to limitations related to its cross-sectional design, providing no data
on the progression of neurological and behavioral performance over time, as
the SGA and AGA infants develop. Nevertheless, the research aimed to detect
alterations during the first days of life in neonates by means of a scale validated
to assess the neurobehavior of babies exposed to risk situations. Assessing
this group of SGA children using the Neonatal Intensive Care Unit Network Neurobehavioral
Scale adds objective results to the literature regarding analysis of predefined
areas of neurological performance and behavior soon after birth. This period
is crucial for establishing healthy family emotional bonds, particularly between
the mother and her baby.

Acknowledgements

To the neonatologists
Cristiane Balut, Samira J. Cardo and Silvana P. M. Amaral for their help with
the data collection. To the Hospital Municipal Maternidade Escola Dr. Mário
de Moraes Altenfelder Silva for making it possible to conduct the study. To
Fapesp for the resources needed to carry out this research.

10. da Silva ES, Nunes ML. The influence of gestational age and birth weight in the clinical assessment of the muscle tone of healthy term and preterm newborns. Arq Neuropsiquiatr. 2005;63:956-62. [ Links ]